It has been firmly established that enantiomers with (S)-configuration of chiral derivatives of .alpha.-phenyl-propionic acid, as well as those of some other .alpha.-heteroaryl-propionic acids, possess predominant, if not exclusive, anti-inflammatory activity.
The resolution of the racemates has been successfully accomplished using both physical and chemical techniques.
Chromatographic separation has been carried out using a variety of substrates.
Coutts et. al. investigated enantiomeric mixtures of nonsteroidal anti-inflammatory drugs (NSAIDs). They discovered that these readily react with (+)- or (-)-amphetamine (AM) in the presence of 1,1'-carbonyldiimidazole. The resulting NSAID-AM diastereoisomeric amides are easily separated by gas chromatography (GC) or by a fused silica ME silicone capillary column. See Development of Drugs in Modern Medicine, 232-6, Edited by Gorrod et. al., Herwood, Chichester, U.K. (1986).
Profen derivatives and some other acidic compounds were resolved by using HPLC with an ovomucoid-conjugated column. The retention of acidic compounds was markedly reduced by the addition of sodium octane sulfonate, while that of amines was reduced by a cationic ion-pairing agent. The ovomucoid-conjugated column exhibited the best chiral recognition ability when the protein molecule was in a state as close as possible to its native form. See Miwa et. al., J. Chromatog., 408, 316-22 (1987).
In Okamota et. al., Chirality, 1(3) 239-42 (1989), the direct optical resolution of anti-inflammatory drugs such as ibuprofen, ketoprofen, and flurbiprofen acid was attempted by HPLC using tris(3,5-dimethylphenylcarbamate)s of cellulose and amylose as chiral stationary phases. Although ibuprofen was not sufficiently resolved, the other three 2-arylpropionic acids were completely resolved by the amylose derivative. Ibuprofen was resolved as the anilide derivative.
Rendic et. al., Chimia, 29(4) 170-172 (1975) describes the resolution of ketoprofen by (R)-.alpha.-phenylethylamine. The products were separated by column chromatography on silica.
However, chromatographic separations, while useful as an analytical tool, are not typically capable of producing large amounts of materials for commercial utility.
Chemical separation is described, for example, in U.S. Pat. No. 4,209,638. A diastereomeric mixture of a salt of 2-arylpropionic acid and an inert liquid organic diluent was heated to at least 80.degree. C. So much salt was used that part remained undissolved in the diluent. Heating was continued until part of one of the optical isomers of the acid component was resolved to its enantiomer by salt formation. The acid component was then separated. The process requires, in addition to a considerable volume of solvent, relatively high temperatures and, in some cases, the application of pressure also being necessary during operation. Nevertheless, the purity of the obtained product leaves something to be desired. The process is both space-consuming and time-consuming, and therefore runs into difficulties on the industrial scale
The object of the present invention is to provide an efficient and practical process for the separation of a racemic mixture of ketoprofen [(.+-.)-.alpha.-(3-benzoylphenyl)propionic acid] into its individual enantiomeric forms, particularly the S(+) form.